Hg(OTf)2-catalyzed vinylogous semi-pinacol rearrangement leading to 1,4-dihydroquinolines

Article abstract of DOI:10.1021/ol2034492

An efficient method for the construction of dihydroquinoline derivatives possessing a quaternary carbon center is developed by an application of Hg(OTf)₂-catalyzed vinylogous semi-pinacol-type rearrangement. The reaction was found to be specifi

Full text of DOI:10.1021/ol2034492

ORGANIC
LETTERS
2012
Vol. 14, No. 5
1222–1225
Hg(OTf)2-Catalyzed Vinylogous
Semi-Pinacol Rearrangement
Leading to 1,4-Dihydroquinolines
Kosuke Namba,*,† Michika Kanaki,† Hiroki Suto,† Mugio Nishizawa,‡ and
Keiji Tanino*,†
Division of Chemistry, Graduate School of Science, Hokkaido University, Kita-ku,
Sapporo 060-0810, Japan, and Faculty of Pharmaceutical Science,
Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
namba@mail.sci.hokudai.ac.jp; ktanino@sci.hokudai.ac.jp
Received December 26, 2011
ABSTRACT
An efficient method for the construction of dihydroquinoline derivatives possessing a quaternary carbon center is developed by an application of
Hg(OTf)2-catalyzed vinylogous semi-pinacol-type rearrangement. The reaction was found to be specifically catalyzed by mercury salt and to
proceed via a bicyclic aminal.
Catalytic synthesis of hydroquinoline derivatives, which
are commonly found in biologically active compounds, is
of great interest for academic and industrial research.1 The
transition-metal-catalyzed syntheses of hydroquinoline
derivatives have been mainly based on (i) a direct addition
of the anilino nitrogens to inner alkynes and alkenes,2
(ii) aza-Michael addition of anilinoenone derivatives,3
(iii) FriedelꢀCrafts type cyclization of N-alkenyl and
alkynyl anilines,4 (iv) intramolecular coupling of 2-haloa-
niline derivatives,5 and so on6 (Scheme 1). We also recently
reported the Hg(OTf)2-catalyzed cyclization of N-tosyla-
nilino allylic alcohol or methyl vinyl ether giving rise to
1,2,3,4-tetrahydroquinoline derivatives or 1,4-dihydroqui-
noline derivatives, respectively.7 However, although the
1,2,3,4-tetrahydroquinoline derivatives were obtained in
excellent yield at room temperature, the cyclization reac-
tion leading to 1,4-dihydroquinoline derivative did not
proceed smoothly even at 110 °C in toluene. Similarly, although
many examples of the catalytic synthesis of hydroquino-
line derivatives have been reported,2ꢀ6 there have been
few examples of the 1,4-dihydroquinoline derivatives.8
† Hokkaido University.
‡ Tokushima Bunri University.
(1) (a) Balasubramanian, M.; Keay, J. G. In Comprehensive Hetero-
cyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon Press: Oxford, 1996; Vol. 5, Chapter 5.06, p 245. (b) Patil, N. T.;
Singh, V. J. Organomet. Chem. 2011, 696, 419. (c) Johannsen, M.;
€
Jørgensen, K. A. Chem. Rev. 1998, 98, 1689. (d) Muller, T. E.; Beller,
M. Chem. Rev. 1998, 98, 675.
(5) For selected recent examples: (a) Lu, Z.; Hu, C.; Guo, J.; Cui, Y.;
Jia, Y. Org. Lett. 2010, 12, 480. (b) Liu, P.; Huang, L.; Lu, Y.;
Dilmeghani, M.; Baum, J.; Xiang, T.; Adams, J.; Tasker, A.; Larsen,
R.; Faul, M. M. Tetrahedron Lett. 2007, 48, 2307. (c) Lautens, M.;
(2) For selected recent examples: (a) Jiang, F.; Wu, Z.; Zhang, W.
Tetrahedron 2011, 67, 1501. (b) Okuro, K.; Alper, H. Tetrahedron Lett.
2010, 51, 4959. (c) Mancheno, D. E.; Thornton, A. R.; Stoll, A. H.;
Kong, A.; Blakey, S. B. Org. Lett. 2010, 12, 4110. (d) Han, Z.-Y.; Chen,
Z.-H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 9182.
(3) For selected recent examples: (a) Liu, X.; Lu, Y. Org. Lett. 2010,
12, 5592. (b) Saito, A.; Kasai, J.; Fukaya, H.; Hanazawa, Y. J. Org.
Chem. 2009, 74, 5644. (c) Lee, J. I.; Youn, J. S. Bull. Korean Chem. Soc.
2008, 29, 1853. (d) Kumar, K. H.; Muralidharan, D.; Perumal, P. T.
Synthesis 2004, 63.
ꢀ
Tayama, E.; Herse, C. J. Am. Chem. Soc. 2005, 127, 72. (d) Sole, D.;
ꢀ
Vallverdu, L.; Solans, X.; Font-Bardia, M.; Bonjoch, J. J. Am. Chem.
Soc. 2003, 125, 1587.
(6) (a) Nakao, Y.; Ebata, S.; Yada, A.; Hiyama, T.; Ikawa, M.;
Ogoshi, S. J. Am. Chem. Soc. 2008, 130, 12874. (b) Santos, L. S.; Pilli,
R. A. Synthesis 2002, 87.
(7) Namba, K.; Nakagawa, Y.; Yamamoto, H.; Imagawa, H.; Nishizawa,
M. Synlett 2008, 1719.
(8) (a) Watanabe, T.; Oishi, T.; Fujii, N.; Ohno, H. Org. Lett. 2007, 9,
4821. (b) Yoshino, Y.; Kurahashi, T.; Matsubara, S. J. Am. Chem. Soc.
2009, 131, 7494.
(4) (a) Giera, D. S.; Schneider, C. Org. Lett. 2010, 12, 4884.
(b) Sizhuo, K. X.; Li, W. P.; Li, X.; Yang, Z.; An, X.; Guo, C.-C.;
Tan, Z. Tetrahedron Lett. 2010, 51, 4466. (c) Youn, S. W.; Pastline, S. J.;
Sames, D. Org. Lett. 2004, 6, 581.
r
10.1021/ol2034492
Published on Web 02/16/2012
2012 American Chemical Society

Furthermore, a common synthetic method based on the
reduction of the quinolines can only be applied to a limited
range of substrates.9 Therefore, we attempted to establish
an efficient catalytic method for the preparation of 1,4-
dihydroquinoline derivatives using a new approach dis-
tinct from the conventional methods described above. Our
plan was to apply vinylogous semi-pinacol rearrangement10
to N-tosylanilinoenal derivatives 4. Itwas expectedthatthe
metal-catalyzed direct addition of a sulfonamide group to
the alkene would be prevented due to the steric hindrance,
and seven-membered ring intermediate 5 would be formed
by the condensation of sulfonamide with aldehyde. The
iminium cation 5 was considered to have undergone the
rearrangement to give the 1,4-dihydroquinoline deriva-
tives 6 as depicted in Scheme 1. It is especially noteworthy
that the rearrangement reaction simultaneously con-
structed a quaternary carbon center at the C4 position.
Although there have been several examples of the synthesis
of 1,4-dihydroquinolines possessing a quaternary carbon
center atthe C4 position,11 the developmentof the catalytic
synthesis is a challenging subject. Thus, we describe herein
the efficient catalytic synthesis of 1,4-dihydroquinoline
derivatives possessing a quaternary carbon center.
Table 1. Investigation of the Catalysts Leading to 1,4-Dihy-
droquinoline 9
yielda
entry
catalyst
mol % temp (°C) time (h)
8
9
1
2
3
4c
5
6
7
TiCl4
10
5
40
40
40
40
40
40
40
70
40
rt
6
quant
81
EtAlCl2
6.5
6
BF3 OEt2
10
10
5
81
3
TMSOTf
Sc(OTf)3
Cu(OTf)2
AgOTf
4.5
82
8
11
98
5
6
7
95
10
50
10
1
96
8b,c PdCl2(MeCN)2
28
9
67
33
90
98
9
Hg(OTFA)2
Hg(OTf)2
10
11
12
0.1
5.5
24
TfOH
1
rt
80
89
AuClPPh3/AgSbF6
5
rt
a Isolated yield. b The reaction was conducted in THF. c NMR yield
using pyrazine as an internal standard.
Scheme 1. Synthetic Approach to the 1,4-Dihydroquinolines
the condensation to give hemiaminal 8, formation of the
iminium cation 5 was not straightforward. Similarly, the use
of other catalysts such as EtAlCl2, BF3 OEt2, Sc(OTf)3,
3
Cu(OTf)2, and AgOTf also gave only hemiaminal 8 (entries
2, 3, 5, 6, 7), and the case of TMSOTf and 50 mol % of
PdCl2(MeCN)2 at 70 °C provided a small amount of 9 along
with hemiaminal 8 (entries 4, 8). In clear contrast, treatment
of the acetal 7 with 10 mol % of mercury trifluoroacetate at
40 °C afforded 9 in 90% yield (entry 9). Furthermore, when
Hg(OTf)2 was used as a highly reactive mercury salt, the
rearrangement reaction proceeded smoothly even under the
condition of 1 mol % of Hg(OTf)2 at room temperature to
give 9 in 98% yield (entry 10). Additionally, treatment of 7
with 1 mol % of TfOH afforded only hemiaminal 8, indicat-
ing that the Hg(OTf)2 is the real catalytic species of this
rearrangement reaction (entry 11). Finally, we examined a
gold catalyst because its reactivity is similar to that of the
mercury catalyst. However, the gold catalyst gave only the
hemiaminal 8, and the formation of 9 was not detected (entry
12). Therefore, we found that the rearrangement reaction of
acetal 7 leading to dihydroquinoline derivatives 9 is the
particular reaction of mercury catalysts. Recently, mercury
catalysis has demonstrated their unieque powerfulness in a
variety of transformations.12 This vinylogous semi-pinacol
We began the investigation of the vinylogous semi-
pinacol rearrangement reaction with acetal 7 due to its
ready availability. In fact, we were able to obtain acetal 7
from 2-cyano-N-tosylaniline in just two steps (see Supporting
Information). Treatment of the acetal 7 with 10 mol % of
TiCl4 as a typical Lewis acid at 40 °C afforded a hemiaminal 8
in quantitative yield, and the rearrangement product 9 was
not detected (Table 1, entry 1). Although the TiCl4 induced
(9) Rabideau, P. W.; Marcinow, Z. Organic Reactions; Paquette, L. A.,
Ed.; John Wiley & Sons, Inc.: New York, 1992; 42, pp 3ꢀ320.
(10) For selected examples of semi-pinacol rearrangement: (a) Song,
Z.-L.; Fan, C.-A.; Tu, Y.-Q. Chem. Rev. 2011, 111, 7523. (b) Zhang,
Q.-W.; Fan, C.-A.; Zhang, H.-J.; Tu, Y.-Q.; Zhao, Y.-M.; Gu, P.; Chen,
Z.-M. Angew. Chem., Int. Ed 2009, 48, 8572. (c) Wang, B.; Tu, Y.-Q. Acc.
Chem. Res. 2011, 44, 1207.
(11) (a) Clayden, J.; Hamilton, S. D.; Mohammed, R. T. Org. Lett. 2005,
7, 3673. (b) Lin, H.; Ng, F. W.; Danishefsky, S. J. Tetrahedron Lett. 2002, 43,
549. (c) Otsuji, Y.; Yutani, K.; Imoto, E. Bull. Chem. Soc. Jpn. 1971, 44, 520.
(12) For a review, see: Nishizawa, M.; Imagawa, H.; Yamamoto, H.
Org. Biomol. Chem. 2010, 8, 511. For selected recent examples: (a) Zhou,
F.; Cao, Z.-Y.; Zhang, J.; Yang, H.-B.; Zhou, J. Chem. Asisan J. 2012, 7,
233. (b) Cao, Z.-Y.; Zhang, Y.; Ji, C.-B.; Zhou, J. Org. Lett. 2011, 13,
3178. (c) Ravindar, K.; Reddy, M. S.; Deslongchamps, P. Org. Lett.
2011, 13, 3178. (d) Yamamoto, H.; Sasaki, I.; Hirai, Y.; Namba, K.;
Imagawa, H.; Nishizawa, M. Angew. Chem., Int. Ed. 2009, 48, 1244.
(e) Namba, K.; Kaihara, Y.; Yamamoto, H.; Imagawa, H.; Tanino, K.;
Williams, R. M.; Nishizawa, M. Chem.;Eur. J. 2009, 15, 6560.
Org. Lett., Vol. 14, No. 5, 2012
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Table 2. Hg(OTf)2-Catalyzed Vinylogous Semi-Pinacol Type
Rearrangement of the Various Substrates
Figure 1. ORTEP of the molecular structure of 9.
rearrangement reaction is also a good example of usefulness
of mercury catalyst. The structure of 9 was unambiguously
confirmed by an X-ray diffraction study (Figure 1).
Meanwhile, treatment of hemiaminal 8 with 1 mol % of
Hg(OTf)2 afforded 9 in 91% yield, and 8 was proven to be
the intermediate of the vinylogous semi-pinacol rearrange-
ment reaction (Scheme 2). Therefore, we proposed that the
reaction is likely to be initiated from a π-complex A. The
migration of an aryl group assisted by the electron dona-
tion of the hemiaminal moiety leads to organomercuric
tosyl iminium cation B, which undergoes the smooth
demercuration to regenerate Hg(OTf)2 catalyst, and the
1,4-dihydroquinoline derivative 9 is obtained. The con-
formation of hemiaminal 8 is considered to be suitable for
the rearrangement of aryl group due to the better orbital
overlap depicted as A0 in Scheme 2.
Scheme 2. Proposed Reaction Mechanism
Scheme 3. Attempts at Performing Rearrangement Reactions
without the Formation of Cyclic Hemiaminal
Thus, we investigated the necessity of cyclic hemiaminal
formation for the rearrangement (Scheme 3). Treatment of
acetal 10, not possessing a tosylamide group, with 5 mol %
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Org. Lett., Vol. 14, No. 5, 2012

of Hg(OTf)2 at 40 °C for 1.5 h did not afford a rearrange-
ment product 11, and the starting compound 10 was
recovered in 59% yield after 1.5 h. The similar reaction
of hemiacetal analogue 12 also did not proceed to give 13,
although a similar electron donating effect was expected.
Therefore, we confirmed that the formation of the seven-
membered cyclic hemiacetal played a significant role for
the rearrangement leading to the dihydroquinoline deriva-
tives possessing a quaternary carbon center.
the additional 3 mol % of Hg(OTf)2 in dichloromethane at
40°C gave31in85% yield (entry 10). Finally, weexamined
a similar rearrangement reaction of phenol derivatives.
Treatment of 33 with 3 mol % of Hg(OTf)2 afforded a
small amount of rearrangement product 34 and benzofuran
derivative 35 as a major product, in later of which was
formed by a direct oxymercuration reaction (entry 11).
Thus, the phenol 33 was first converted to bicyclic acetal 36
by treatment with PPTS before the rearrangement
reaction. Treatment of bicyclic acetal 36 with 3 mol % of
Hg(OTf)2 at room temperature induced only the rearran-
gement reaction to give the desired chromene derivative 34
in 97% yield (entry 12). Thus, the rearrangement reaction
of the phenol derivative was also proven to proceed via
bicyclic acetal as an intermediate.
In this study, an efficient method for the construction of
1,4-dihydroquinoline and 4H-chromene derivatives pos-
sessing a quaternary carbon center was established. We
elucidated that the reactions proceed via seven-membered
bicyclic hemiaminal and are specifically catalyzed by mer-
cury salt. Our current study clearly demonstrated that this
catalytic rearrangement protocol is applicable to the var-
ious tosylanilinoallyl acetals and is a powerful synthetic
method for the construction of complex carbon frame-
works with similarities to natural products. The applica-
tion of this rearrangement reaction is currently underway
in our laboratory.
Having established an optimized condition for the viny-
logous semi-pinacol rearrangement, we next examined the
reactions with various substrates (Table 2).
The reactions of similar analogues that possess a methyl
group on the aromatic ring (14 and 16) and other side
chains such as a methyl group (18),13 isopropyl group (20),
and tert-butyl group (22) also provided the correspond-
ing rearrangement products in good yields, although the
slightly more than 1 mol % of Hg(OTf)2 was needed to
complete the conversion (entries 1ꢀ5). The reaction of 24
possessing an electron-withdrawing group was slow, and
treatment of 10 mol % of Hg(OTf)2 at 110 °C afforded the
ketone 25 in 70% yield (entry 6). The reaction of triiso-
propylsilyl ether derivatives 26 gave the desired 27 in 40%
yield, along with the byproducts derived from the desilyla-
tion of 27 (entry 7). The reaction of the seven-membered
ring fused system 28 needed 5 mol % of Hg(OTf)2 to give
29 in 83% yield (entry 8). The reaction of an aryl fused
system 30 with 2 mol % of Hg(OTf)2 at room tempera-
ture stopped at the hemiaminal due to the stability of
the conjugated alkene, and an additional treatment of
Hg(OTf)2 at 40 °C afforded a mixture of the desired 31
and 7,8-dihydrobenzo[k]phenanthridine 3214 (entry 9).
Thus, in situ-generated methanol was evacuated by a vacuum
after the formation of hemiaminal, and then treatment of
Acknowledgment. We thank professor Tamotsu Inabe
(Hokkaido University) for the X-ray analysis of 9. This
work was partially supported by the Global COE program
(Project No. B01: Catalysis as the Basis for Innovation in
MaterialScience) andGrant-in-Aid forScientific Research
on Innovative Areas (Project No. 2105: Organic Synthesis
Based on Reaction Integration) from the Ministry of
Education, Culture, Sports, Science, and Technology,
Japan.
(13) The methyl analogue automatically formed the cyclic hemiam-
inal 18 just after synthesis of the starting material.
(14) Addition of methanol to the methyl ketone moiety of 31 was
assumed to induce the aromatization to give 32. For the spectral data of
32, see: Banwell, M. G.; Lupton, D. W.; Ma, X.; Renner, J.; Sydnes,
M. O. Org. Lett. 2004, 6, 2741–2744.
Supporting Information Available. Experimental de-
tails, and 1H and 13C NMR spectra of each each rearran-
gement product. This material is available free of charge
via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 5, 2012
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